Orally inhalable formulations are widely used for the administration of medications via the pulmonary route. Such medications are generally administered for treatment or prophylaxis of pulmonary conditions, the commonest of which include, for example, asthma and chronic obstructive pulmonary disorder. Also, drugs for systemic use may in appropriate circumstances be administered by inhalation.
The efficacy and systemic exposure (lung bioavailability) of an inhaled drug depends on the site of deposition and the physicochemical properties of the drug formulation. Drug particles that deposit in the peripheral non-ciliated regions of the respiratory tract must dissolve before metabolism or transport across the lung membrane can occur. Dissolution is therefore a prerequisite for cellular uptake and/or absorption via the lungs. Simulations suggest dissolution rate is the main driver for drug retention in the lung. At present, however, there is no pharmacopeial method which exists to determine the in vitro dissolution rate of aerosols generated by inhaled products.
Dissolution testing is an important tool in the determination of the bioavailability of many drugs. Standardized dissolution test methods are available for solid dosage forms such as tablets and capsules. Such methods are widely used in quality control and to determine correlations with in vivo release profiles. They are a particularly important tool where there is a necessity to demonstrate the equivalence of different formulations, for example in demonstrating the equivalence of generic drugs to an approved formulation. To date, however, there is no universally accepted method for estimating the dissolution behaviour of inhaled active ingredient dosage forms. This presents an obstacle to the development of reliably bioequivalent formulations. The absence of a pharmacopeial method in particular presents an obstacle to reliably and reproducibly demonstrating bioequivalence of new inhalable generic drugs with pre-existing registered products, and thus renders the obtaining of authorisation for inhalable drugs more difficult than in the case of most oral or injectable drug formulations.
Studies have indicated good correlation between in vivo based measurements of total lung deposition and in vitro measurements of lung dose. Thus, there is a need to collect a representative lung dose for dissolution studies (e.g. ex-cast dose, impactor stage mass, dose below a defined impactor stage etc.). For all reported filter collection systems, there is a slower dissolution rate with increasing collected mass of a given formulation by varying the number of actuations. This effect is thought to be due to formation of in-situ agglomerates created on the filter upon dose collection which in view of the smaller area/volume ratio reduces the exposure of the drug to the dissolution media during dissolution. Since the dissolution characteristics ought to be independent of the method of collection and the number of actuations, the absence of consistency in the dissolution rates is thought to be attributable to an artefact of the collection process. The significant variation observed in dissolution behaviour limits sensitivity and creates challenges when comparing formulations with differing fine particle mass of the same product.
In any dissolution method, two key steps are the collection of the inhalable dose to be dissolved and the dissolution step of dissolving the collected dose. In order to provide a reliable prediction of the dose that will be dissolved in vivo, the sample used in the dissolution step should reflect the dose that, in practice, would be inhaled. In some known collection methods, the inhalable dose is collected on a filter in an inertial impactor.
A reliable method for estimating the dissolution behaviour of inhaled products would have a number of applications. It could be applied in the context of quality control as a tool for evaluating material properties, and processing effects on active ingredient dissolution. It would be of general application in collection and dissolution studies of the aerosolised dose (e.g. determining ex cast, Impactor stage mass etc.). The most important potential application would be to provide an in vitro-in vivo correlation (IVIVC) technique. An IVIVC technique would have the potential to permit reliable evaluation of dissolution behaviour of generic version of pulmonary drugs such as those evaluated on the basis of showing comparability with existing authorised products, thus reducing a current obstacle to the satisfactory evaluation of, for example, generic versions of inhalable drugs.
For a QC testing tool, dissolution models should focus on discriminatory capability, ruggedness and stability.
For use in the above applications, it is critical to develop a dissolution method which can be validated and have the ability to assess drug product quality attributes.